SPE-UHPLC-ESI-MS/MS Analysis of Cocaine and Its Metabolites in Conventional and Alternative Biological Specimens: Application to Real Samples.

An increase in cocaine abuse has been observed globally since the past decade. Cocaine is among the commonly abused stimulants used for recreational purposes. In this study, the SPE-UHPLC-MS/MS method was developed and validated to be applied on real specimens of 20 chronic cocaine abusers to quantify cocaine/metabolites in conventional as well as alternative biological matrices. Cocaine was extracted from biological specimens using solid-phase extraction followed by liquid chromatography tandem mass spectrometry analysis. Chromatographic separation was achieved on a Poroshell120EC-18 column (2.1 mm × 50 mm, 2.7 µm particle size) using water-acetonitrile in 0.1% formic acid as a mobile phase in gradient elution mode. The flow rate of the mobile phase was 0.5 mL/min with a gradient varying the percentage of acetonitrile linearity ranging 15-95% in 6.0 min acquisition time, and the injection volume was set at 5 µL. Positive electrospray ionization with multireaction ion monitoring mode using two ion transitions for cocaine/metabolites and one for cocaine-d3 was employed. The quantification method demonstrated good linear ranges of 0.025-250 ng/mL in blood, urine, and oral fluid (ng/mg for hair and nail) with a ≥0.991% determination coefficient. The detection limit and lower quantification limit were 0.005 and 0.025 ng/mL in all matrices, respectively. The mean extraction recovery and ionization suppression ranged from 89.3 to 99.8% and -4.6 to -14.4% in the studied matrices. Within-run and between-days precisions were 1.8-7.2% and 1.9-6.1%, respectively. This study will not only help in quantifying cocaine/metabolites in alternative specimens (hair, nail, and oral fluid) but also guide clinical and forensic toxicologists in interpretation of exhumation cases. Furthermore, multiple specimens' analyses can be of significance in estimating the time/manner of drug exposure, in confirming the results of laboratories in cases of doubtful clinical histories, or in aiding medico-legal investigations.

Determining Ideal Management for Patients With Coexisting Prolactinomas and Psychiatric Symptoms: A Systematic Review.

OBJECTIVE: Prolactinomas-pituitary tumors that overproduce prolactin-can cause various troublesome symptoms. Dopamine agonists (DAs) reduce prolactin production in the prolactin pathway, making them the first-line treatment for prolactinomas. However, the main side effect of DA treatment, hyperdopaminergia, is an explicit etiology for psychiatric side effects. Psychiatric conditions are often treated with dopamine antagonists, which can induce hyperprolactinemia. This presents a challenge for patients with both a prolactinoma and a preexisting psychiatric condition, as treatment of one condition could worsen the other. This review seeks to identify an adequate therapeutic regimen for patients with coexisting prolactinomas and psychiatric symptoms. METHODS: This review examined PubMed citations from 1960 to 2023 published in English and involving human subjects. Case reports, case series, and cohort studies involving patients with concomitant prolactinomas and psychiatric symptoms, as validated by brain imaging, serologic prolactin levels, and medical history or chart reports of psychiatric symptoms, were included. RESULTS: Thematic analysis included 23 reports involving 42 participants; 27 of the 42 patients experienced a significant reduction in prolactin levels and psychiatric symptoms (64%). Treatment of those 42 patients included discontinuing or altering antipsychotic/dopamine antagonist therapy or discontinuing DA therapy to reduce psychiatric symptoms, with surgery or radiation postpharmacotherapy as a last-line strategy. However, in some cases (reported in Tables 2 to 4), either psychiatric or prolactin-related symptoms recurred despite adjustment. CONCLUSIONS: Clinicians may find it beneficial to prioritize specific antipsychotics (aripiprazole, olanzapine, ziprasidone, or clozapine) over others (risperidone, thioridazine, thiothixene, and remoxipride). Discontinuing DA medication at least periodically until the patient's condition improves may also be advisable. If these 2 initial approaches do not yield a significant improvement in symptom management, surgery or radiation therapy may be considered. As patients may respond differently to these therapies, our study still recommends a patient-centered approach.

The impact of green FDI on environmental quality in less developed countries: A case study of load capacity factor based on PCSE and FGLS techniques.

This paper examines the effect of green foreign direct investment (GFDI) on environmental quality (EQ) in 34 less-developed countries (LDCs) from 2003 to 2021. We analyze balanced panel data using Feasible Generalized Least Squares (FGLS) and Panel-Corrected Standard Errors (PCSE). Our findings reveal several vital insights: (1) GFDI helps improve EQ. (2) Environmental costs associated with economic growth are negative. (3) Trade openness positively influences EQ. (4) EQ is enhanced by institutional quality, energy use, and population expansion in the chosen countries. (5) The existence of a U-shaped curve was established. This is valuable to the relatively scanty literature on GFDI, especially in LDCs. To the best of our awareness, this study simultaneously employs the Load Capacity Factor (LCF) and Total Value of Announced Greenfield projects as proxies for environmental sustainability and GFDI for the first time. Secondly, incorporating PCSE and FGLS models in this context is an innovative methodological strategy. The present research work provides to the existing theoretical and empirical discussions on GFDI and EQ and has practical implications that inform policy-making.

Testicular Cancer and Paraneoplastic Encephalitis: A Review of the Current Literature.

INTRODUCTION: Paraneoplastic encephalitis (PE) represents a rare but significant complication in patients with testicular cancer (TC). Given the paucity of comprehensive literature on this topic, our review seeks to consolidate current knowledge and provide evidence-based recommendations for the diagnosis, prognosis, and management of PE in the context of TC. MATERIALS AND METHODS: In adherence to PRISMA guidelines, a systematic literature review was conducted from 1950 to April 2024 using PubMed. The search focused on articles where TC was identified as the primary etiology of PE. The Mixed Methods Appraisal Tool and the Oxford Centre for Evidence-Based Medicine's levels of evidence tool were employed for assessing study quality, and a thematic analysis was conducted to identify trends and patterns. RESULTS: Out of 91 articles identified, 29 met the inclusion criteria, encompassing 5 retrospective chart reviews, 3 case series, and 22 case reports. Findings indicate that PE symptoms can manifest at any stage of TC-before tumor detection, during treatment, or even years posttreatment. A notable observation was the frequent oversight of microscopic testicular tumors in ultrasound imaging, leading to diagnostic delays. The outcomes of PE in the context of TC were diverse, reflecting the heterogeneity of the studies included. CONCLUSION: PE, although rare, is a critical consideration in patients with TC presenting with neuropsychiatric symptoms. Early recognition and appropriate diagnostic workup, including consideration for microscopic neoplasms, are essential for timely intervention and improved patient outcomes.

Mutational spectrum of CFTR in cystic fibrosis patients with gastrointestinal and hepatobiliary manifestations.

BACKGROUND: Cystic fibrosis (CF) is a rare and debilitating autosomal recessive disorder. It hampers the normal function of various organs and causes severe damage to the lungs, and digestive system leading to recurring pneumonia. Cf also affects reproductive health eventually may cause infertility. The disease manifests due to genetic aberrations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This study aimed to screen for CFTR gene variants in Pakistani CF patients representing variable phenotypes. METHODS: Clinical exome and Sanger sequencing were performed after clinical characterization of 25 suspected cases of CF (CF1-CF25). ACMG guidelines were followed to interpret the clinical significance of the identified variants. RESULTS: Clinical investigations revealed common phenotypes such as pancreatic insufficiency, chest infections, chronic liver and lung diseases. Some patients also displayed symptoms like gastroesophageal reflux disease (GERD), neonatal cholestasis, acrodermatitis, diabetes mellitus, and abnormal malabsorptive stools. Genetic analysis of the 25 CF patients identified deleterious variants in the CFTR gene. Notably, 12% of patients showed compound heterozygous variants, while 88% had homozygous variants. The most prevalent variant was p. (Met1Thr or Met1?) at 24%, previously not reported in the Pakistani population. The second most common variant was p. (Phe508del) at 16%. Other variants, including p. (Leu218*), p. (Tyr569Asp), p. (Glu585Ter), and p. (Arg1162*) were also identified in the present study. Genetic analysis of one of the present patients showed a pathogenic variant in G6PD in addition to CFTR. CONCLUSION: The study reports novel and reported variants in the CFTR gene in CF patients in Pakistani population having distinct phenotypes. It also emphasizes screening suspected Pakistani CF patients for the p. (Met1Thr) variant because of its increased observance and prevalence in the study. Moreover, the findings also signify searching for additional pathogenic variants in the genome of CF patients, which may modify the phenotypes. The findings contribute valuable information for the diagnosis, genetic counseling, and potential therapeutic strategies for CF patients in Pakistan.

Assessment of occupational musculoskeletal disorders (MSDs) among heavy vehicle drivers.

BACKGROUND: Professional driving requires long hours of work, uncomfortable seats, negotiating rough terrain and highways, and possibly minor repairs and other auxiliary transportation duties. Heavy vehicle drivers driving vehicles such as trucks, bulldozers, etc. due to such working structures are more prone to various musculoskeletal disorders (MSDs) and pain, which is of great concern. OBJECTIVES: In the present study, it is planned to investigate possible ergonomic risk factors such as age, weight, driving exposure, seat suspension systems, lifting heavy weights causing MSDs in drivers of various heavy vehicles. The results of the study are expected to help drivers reduce the risk of MSDs. METHODS: For the present study, the Nordic questionnaire on musculoskeletal disorders was modified and standardized and was administered to the 48 heavy vehicle drivers randomly selected to collect the data. RESULTS: The analysis divulged that over the past 12 months, lower back pain (LBP) emerged as the most dominant pain experienced by 56% of drivers, followed by knee pain (KP) (43%) and neck pain (NP) (39%) respectively. The prevalence of shoulder pain (SP) was observed to be much lower than in previous literature. The logistic regression model further revealed that increasing age, poor suspension system and poor body posture were significantly associated with lower back pain. Additionally, a poor suspension system and lifting heavy weights had significant effect on the drivers' knee pain. CONCLUSION: The results demonstrated the evident necessity for ergonomic consideration in vehicle designing and ergonomic training for heavy vehicle drivers.

An early force prediction control scheme using multimodal sensing of electromyography and digit force signals.

Different grasping gestures result in the change of muscular activity of the forearm muscles. Similarly, the muscular activity changes with a change in grip force while grasping the object. This change in muscular activity, measured by a technique called Electromyography (EMG) is used in the upper limb bionic devices to select the grasping gesture. Previous research studies have shown gesture classification using pattern recognition control schemes. However, the use of EMG signals for force manipulation is less focused, especially during precision grasping. In this study, an early predictive control scheme is designed for the efficient determination of grip force using EMG signals from forearm muscles and digit force signals. The optimal pattern recognition (PR) control schemes are investigated using three different inputs of two signals: EMG signals, digit force signals and a combination of EMG and digit force signals. The features extracted from EMG signals included Slope Sign Change, Willison Amplitude, Auto Regressive Coefficient and Waveform Length. The classifiers used to predict force levels are Random Forest, Gradient Boosting, Linear Discriminant Analysis, Support Vector Machines, k-nearest Neighbors and Decision Tree. The two-fold objectives of early prediction and high classification accuracy of grip force level were obtained using EMG signals and digit force signals as inputs and Random Forest as a classifier. The earliest prediction was possible at 1000 ms from the onset of the gripping of the object with a mean classification accuracy of 90 % for different grasping gestures. Using this approach to study, an early prediction will result in the determination of force level before the object is lifted from the surface. This approach will also result in better biomimetic regulation of the grip force during precision grasp, especially for a population facing vision deficiency.

Examining the relationship between head trauma and opioid use disorder: A systematic review.

OBJECTIVE: To examine recent literature and determine common clinical risk factors between antecedent traumatic brain injury (TBI) and the following development of opioid misuse and provide a framework for clinical identification of at-risk subjects and evaluate potential treatment implications within this association. DESIGN: A comprehensive systematic literature search of PubMed was conducted for articles between 2000 and December 2022. Studies were included if the human participant had any head trauma exposure and any chronic opioid use or dependence. After eligibility criteria were applied, 16 studies were assessed for thematic trends. RESULTS: Opioid use disorder (OUD) risks are heightened in cohorts with head trauma exposed to opioids while in the hospital, specifically with tramadol and oxycodone. Chronic pain was the most common predictor of long-term OUD, and continuous somatic symptoms associated with the TBI can lead to long-term opioid usage. Individuals who present with coexisting psychiatric conditions pose significantly more risk associated with a higher risk of long-term opioid use. CONCLUSION: Findings indicate that therapists and clinicians must consider a risk profile for persons with TBI and follow an integrated care approach to account for mental health, prior substance misuse, presenting somatic symptoms, and current medication regimen during evaluation.

Assessment of pheniramine in alternative biological matrices by liquid chromatography tandem mass spectrometry.

Pheniramine is an over-the-counter antihistamine drug. Its accessibility and low cost made it more popular among drug abusers in Pakistan. In this study, pheniramine was quantified in both conventional and alternative specimens of twenty chronic drug abusers, aged 16-50 years, who were positive for pheniramine in comprehensive toxicological screening for drugs by gas chromatography with mass spectral detection in positive electron impact mode. Pheniramine was extracted from biological specimens using solid phase extraction and liquid chromatography tandem mass spectrometry was employed for quantification. Chromatographic separation was carried out on a Poroshell120EC-18 (2.1 mm × 50 mm × 2.7 µm) column using water-acetonitrile in formic acid (0.1%) mobile phase in gradient elution mode with 500 µL/min flow rate. Positive electrospray ionization mode and multi-reaction monitoring with ion transitions m/z 241.3 → 195.8 and 167.1 for pheniramine and m/z m/z 247.6 → 173.1 for pheniramine-d6 were employed. The quantification method showed good linear ranges of 2-1000 ng/mL in blood, urine, and oral fluid; 2-1000 ng/mg in hair and 5-1000 ng/mg in nail with ≥ 0.985% coefficient of linearity. The retention time of pheniramine was 3.0 ± 0.1 min. The detection and lower quantification limits were 1 ng/mL and 2 ng/mL for blood, urine, oral fluid and hair whereas 2.5 ng/mg and 5 ng/mg for nail, respectively. Mean extraction recovery and ionization suppression ranged 86.3-95.1% and -4.6 to -14.4% in the studied matrices. Intra-day and inter-day precision were 4.1-9.3% and 2.8-11.2%, respectively. Pheniramine levels in specimens of drug abusers were 23-480 ng/mL in blood, 72-735 ng/mL in urine, 25-379 ng/mL in oral fluid, 10-170 ng/mg in hair and 8-86 ng/mg in nail specimens. Alternative specimens are of utmost significance in clinical and medico-legal cases. In this study, authors compared matrix-matched calibration curves to blood calibration curve and obtained results within ± 10%; thereby justifying the use of blood calibration curve for urine, oral fluid, hair, and nail specimens.

Single-Molecule DNA Methylation Reveals Unique Epigenetic Identity Profiles of T Helper Cells.

Both identity and plasticity of CD4 T helper (Th) cells are regulated in part by epigenetic mechanisms. However, a method that reliably and readily profiles DNA base modifications is still needed to finely study Th cell differentiation. Cytosine methylation in CpG context (5mCpG) and cytosine hydroxymethylation (5hmCpG) are DNA modifications that identify stable cell phenotypes, but their potential to characterize intermediate cell transitions has not yet been evaluated. To assess transition states in Th cells, we developed a method to profile Th cell identity using Cas9-targeted single-molecule nanopore sequencing. Targeting as few as 10 selected genomic loci, we were able to distinguish major in vitro polarized murine T cell subtypes, as well as intermediate phenotypes, by their native DNA 5mCpG patterns. Moreover, by using off-target sequences, we were able to infer transcription factor activities relevant to each cell subtype. Detection of 5mCpG and 5hmCpG was validated on intestinal Th17 cells escaping transforming growth factor ß control, using single-molecule adaptive sampling. A total of 21 differentially methylated regions mapping to the 10-gene panel were identified in pathogenic Th17 cells relative to their nonpathogenic counterpart. Hence, our data highlight the potential to exploit native DNA methylation profiling to study physiological and pathological transition states of Th cells.

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Hepatocellular carcinoma (HCC) is one of the most common malignancies and is a major cause of cancer-related mortalities worldwide (Forner et al., 2018; He et al., 2023). Sarcopenia is a syndrome characterized by an accelerated loss of skeletal muscle (SM) mass that may be age-related or the result of malnutrition in cancer patients (Cruz-Jentoft and Sayer, 2019). Preoperative sarcopenia in HCC patients treated with hepatectomy or liver transplantation is an independent risk factor for poor survival (Voron et al., 2015; van Vugt et al., 2016). Previous studies have used various criteria to define sarcopenia, including muscle area and density. However, the lack of standardized diagnostic methods for sarcopenia limits their clinical use. In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) renewed a consensus on the definition of sarcopenia: low muscle strength, loss of muscle quantity, and poor physical performance (Cruz-Jentoft et al., 2019). Radiological imaging-based measurement of muscle quantity or mass is most commonly used to evaluate the degree of sarcopenia. The gold standard is to measure the SM and/or psoas muscle (PM) area using abdominal computed tomography (CT) at the third lumbar vertebra (L3), as it is linearly correlated to whole-body SM mass (van Vugt et al., 2016). According to a "North American Expert Opinion Statement on Sarcopenia," SM index (SMI) is the preferred measure of sarcopenia (Carey et al., 2019). The variability between morphometric muscle indexes revealed that they have different clinical relevance and are generally not applicable to broader populations (Esser et al., 2019).

Synthesis of ZnO and PEG-ZnO nanoparticles (NPs) with controlled size for biological evaluation.

The objective of this research was to produce the smallest possible ZnO nanoparticles through an adapted wet chemical process and subsequently, to fabricate a core-shell structure utilizing polyethylene glycol (PEG) as the shell component. The synthesis, size, and shape of the NPs were confirmed using advanced techniques. The resulting clustered NPs were round and had a size of 9.8 nm. Both plain and core-shell NPs were tested for their antibacterial properties against multi-drug resistant bacteria strains (E. cloacae, E. amnigenus, S. flexneri, S. odorifacae, Citrobacter, and E. coli), with concentrations of 500, 1000, and 1500 µg ml-1 used for testing. Both types of NPs demonstrated antibacterial activity against the tested pathogens, with the core-shell NPs being more effective. The synthesized NPs were biocompatible with human red blood cells, with a low level of hemolysis observed. The biocompatibility of the core-shell NPs was significantly enhanced by the presence of the PEG added as the shell. In addition, their effectiveness as photosensitizers for cancer treatment via photodynamic therapy (PDT) was evaluated. MTT assay was used to evaluate the cytotoxicity of ZnO and PEG-ZnO, and the results showed that these NPs were able to generate ROS inside tumor cells upon irradiation, leading to apoptosis and cell death, making them a promising candidate for PDT.

The deleterious variants of N-acetylgalactosamine-6-sulfatase (GalN6S) enzyme trigger Morquio a syndrome by disrupting protein foldings.

Lysosomal enzymes degrade cellular macromolecules, while their inactivation causes human hereditary metabolic disorders. Mucopolysaccharidosis IVA (MPS IVA; Moquio A syndrome) is one of the lysosomal storage disorders caused by a defective Galactosamine-6-sulfatase (GalN6S) enzyme. In several populations, disease incidence is elevated due to missense mutations brought on by non-synonymous allelic variation in the GalN6S enzyme. Here, we studied the effect of non-synonymous single nucleotide polymorphism (nsSNPs) on the structural dynamics of the GalN6S enzyme and its binding with N-acetylgalactosamine (GalNAc) using all-atom molecular dynamics simulation and an essential dynamics approach. Consequently, in this study, we have identified three functionally disruptive mutations in domain-I and domain-II, that is, S80L, R90W, and S162F, which presumably contribute to post-translational modifications. The study delineated that both domains work cooperatively, and alteration in domain II (S80L, R90W) leads to conformational changes in the catalytic site in domain-I, while mutation S162F mainly provokes higher residual flexibility of domain II. These results show that these mutations impair the hydrophobic core, implying that Morquio A syndrome is caused by misfolding of the GalN6S enzyme. The results also show the instability of the GalN6S-GalNAc complex upon substitution. Overall, the structural dynamics resulting from point mutations give the molecular rationale for Moquio A syndrome and, more importantly, the Mucopolysaccharidoses (MPS) family of diseases, re-establishing MPS IVA as a protein-folding disease.Communicated by Ramaswamy H. Sarma.

Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia.

BACKGROUND: Anophthalmia and microphthalmia are severe developmental ocular disorders that affect the size of the ocular globe and can be unilateral or bilateral. The disease is found in syndromic as well as non-syndromic forms. It is genetically caused by chromosomal aberrations, copy number variations and single gene mutations, along with non-genetic factors such as viral infections, deficiency of vitamin A and an exposure to alcohol or drugs during pregnancy. To date, more than 30 genes having different modes of inheritance patterns are identified as causing anophthalmia and microphthalmia. METHODS: In the present study, a clinical and genetic analysis was performed of six patients with anophthalmia and microphthalmia and/or additional phenotypes of intellectual disability, developmental delay and cerebral palsy from a large consanguineous Pakistani family. Whole exome sequencing followed by data analysis for variants prioritization and validation through Sanger sequencing was performed to identify the disease causing variant(s). American College of Medical Genetics and Genomics (ACMG) guidelines were applied to classify clinical interpretation of the prioritized variants. RESULTS: Clinical investigations revealed that the affected individuals are afflicted with anophthalmia. Three of the patients showed additional phenotype of intellectual disability, developmental delays and other neurological symptoms. Whole exome sequencing of the DNA samples of the affected members in the family identified a novel homozygous stop gain mutation (NM_012186: c.106G>T: p.Glu36*) in Forkhead Box E3 (FOXE3) gene shared by all affected individuals. Moreover, patients segregating additional phenotypes of spastic paraplegia, intellectual disability, hearing loss and microcephaly showed an additional homozygous sequence variant (NM_004722: c.953G>A: p.Arg318Gln) in AP4M1. Sanger sequencing validated the correct segregation of the identified variants in the affected family. ACMG guidelines predicted the variants to be pathogenic. CONCLUSIONS: We have investigated first case of syndromic anophthalmia caused by variants in the FOXE3 and AP4M1. The present findings are helpful for understanding pathological role of the mutations of the genes in syndromic forms of anophthalmia. Furthermore, the study signifies searching for the identification of second variant in families with patients exhibiting variable phenotypes. In addition, the findings will help clinical geneticists, genetic counselors and the affected family with respect to prenatal testing, family planning and genetic counseling.

Deep learning-based radiomics allows for a more accurate assessment of sarcopenia as a prognostic factor in hepatocellular carcinoma / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Hepatocellular carcinoma (HCC) is one of the most common malignancies and is a major cause of cancer-related mortalities worldwide (Forner et al., 2018; He et al., 2023). Sarcopenia is a syndrome characterized by an accelerated loss of skeletal muscle (SM) mass that may be age-related or the result of malnutrition in cancer patients (Cruz-Jentoft and Sayer, 2019). Preoperative sarcopenia in HCC patients treated with hepatectomy or liver transplantation is an independent risk factor for poor survival (Voron et al., 2015; van Vugt et al., 2016). Previous studies have used various criteria to define sarcopenia, including muscle area and density. However, the lack of standardized diagnostic methods for sarcopenia limits their clinical use. In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) renewed a consensus on the definition of sarcopenia: low muscle strength, loss of muscle quantity, and poor physical performance (Cruz-Jentoft et al., 2019). Radiological imaging-based measurement of muscle quantity or mass is most commonly used to evaluate the degree of sarcopenia. The gold standard is to measure the SM and/or psoas muscle (PM) area using abdominal computed tomography (CT) at the third lumbar vertebra (L3), as it is linearly correlated to whole-body SM mass (van Vugt et al., 2016). According to a "North American Expert Opinion Statement on Sarcopenia," SM index (SMI) is the preferred measure of sarcopenia (Carey et al., 2019). The variability between morphometric muscle indexes revealed that they have different clinical relevance and are generally not applicable to broader populations (Esser et al., 2019).

The Effect of Antipsychotics on Prolactinoma Growth: A Radiological and Serological Analysis.

Many antipsychotic (AP) medications work by reducing dopamine levels. As hyperdopaminergia is known to cause psychosis, antipsychotics work to relieve these symptoms by antagonizing dopamine receptors and lowering dopamine levels. Dopamine is also a known negative modulator of the prolactin pathway, which allows for drug agents like dopamine agonists (DAs) to be incredibly effective in managing tumors that secrete excess prolactin (prolactinomas). While the effects of DAs on prolactinoma size and growth have been studied for decades, the effects of APs on prolactinoma size remain to be seen. We hope to investigate the effects of APs on prolactinomas by conducting a thorough PubMed search, including patients with diagnosed prolactinoma on concurrent AP therapy. Our search led to 27 studies with a total of 32 patients. We identified themes regarding seven antipsychotics: risperidone, haloperidol, amisulpride, thioridazine, aripiprazole, olanzapine, and clozapine. Risperidone, haloperidol, amisulpride, and thioridazine caused a significant increase in prolactin in most cases where they were used, and prolactin decreased after their discontinuation. For example, risperidone discontinuation resulted in a decrease in prolactin levels by an average of 66%, while haloperidol, amisulpride, and thioridazine discontinuation lowered prolactin by an average of 82%, 72%, and 89.7%, respectively. However, there were some exceptions in regard to risperidone, haloperidol, and thioridazine, where prolactin levels were not as severely affected. Aripiprazole, olanzapine, and clozapine all had significant reductions in prolactin levels when patients were switched from another antipsychotic, such as risperidone or haloperidol. The average percent decrease in prolactin when switched to aripiprazole was 67.65%, while it was 54.16% and 68% for olanzapine and clozapine, respectively. The effect of individual antipsychotics on prolactinoma size was difficult to ascertain, as imaging was not obtained (or indicated) after every antipsychotic switch, and many patients were taking dopamine agonists concurrently. Therefore, it would be difficult to ascertain which factor affected size more. Also, some patients received surgery or radiotherapy, which completely negated our ability to make any assertions about the effects of certain pharmacological agents. Although it is difficult to ascertain the role that antipsychotic medications play in the formation of prolactinoma, we have found that the cessation of certain antipsychotic medications may lead to a reduction in prolactin levels and possibly the presence of a measurable prolactinoma.

Insulin-induced gene 2 protects against hepatic ischemia-reperfusion injury via metabolic remodeling.

BACKGROUND: Hepatic ischemia-reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. METHODS: Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. RESULTS: Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). CONCLUSIONS: Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

Truncated DNM1 variant underlines developmental delay and epileptic encephalopathy.

Background: Developmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B. Methods: In the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)-based mRNA expression were checked using standard methods. Results: Data analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient. Conclusion: Our finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis.

Role of multi-strain probiotics in preventing severity and frequency of recurrent respiratory tract infections in children.

BACKGROUND: Respiratory tract infections are among the most common infections in the pediatric population throughout the globe. Globally around 20% of all deaths in children below 5 years of age are secondary to acute respiratory infections, mostly pneumonia. Probiotics are live microorganisms that when administered in adequate amounts confer a health benefit on the host. Their mechanism in preventing respiratory tract infections is not known but it is thought that probiotics act by modulating the immune system. This study was conducted to find out whether using probiotics is effective in decreasing the severity and frequency of recurrent respiratory tract infections or not. METHODS: A Quasi-experimental study was conducted at the Pediatric Medicine Department of Abbassi Shaheed Hospital Karachi during 2021-2022. The study was approved by the institutional ethical review committee i.e. advanced studies and research board (ASRB). The sampling technique was non-probability consecutive sampling and the sample size was 70 patients with recurrent respiratory tract infections, aged six months to 12 years of age. All enrolled children were given probiotics containing Bifidobacterium, Lactobacillus Acidophilus for two weeks. Data were analyzed by using SPSS version 22. A p-value of < 0.05 was considered statistically significant. RESULTS: Out of 70 children with recurrent respiratory tract infections, 39 (55.71%) were male and 31 (44.29%) female. Around 75% of the children were below five years of age. The most common presenting complaint was fever (72.86%), followed by cough (68.57%), wheezes (45.71%) and nasal discharge/sneezing (32.86%), respectively. The most common RRTI was infectious rhinitis (30% of the cases), otitis media (24%) and pharyngitis/tonsillitis (21%). After giving probiotics for two weeks most significant decrease was found in recurrent infectious rhinitis (p-value 0.02), recurrent otitis media (p-value 0.03) and recurrent bronchiolitis (p-value 0.05) over the next six months. CONCLUSION: The results of our study indicate that the administration of probiotics reduces recurrent respiratory tract infections among children. This six months trial has demonstrated that there was a significant decline in respiratory symptoms among study participants. This study also observed a significant decrease in respiratory diseases during the follow-up.

Correction: Appealing perspectives of the structural, electronic, elastic and optical properties of LiRCl3 (R = Be and Mg) halide perovskites: a DFT study.

[This corrects the article DOI: 10.1039/D3RA02640J.].